U.S. Pat. No. 5,100,889 to Misra et al discloses 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs which are thromboxane A.sub.2 (TXA.sub.2) receptor antagonists or combined thromboxane A.sub.2 receptor antagonist/thromboxane synthetase inhibitors useful, for example, in the treatment of thrombotic and/or vasospastic diseases, and have good duration of action. Examples of compounds disclosed in Misra et al have the structural formula I ##STR2## and including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;
R.sup.1 is hydrogen, lower alkyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl, or amide ##STR3## wherein t is 1 to 12 and R.sub.a is lower alkyl, aryl, cycloalkyl, or cycloalkylalkyl); PA1 R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or R.sup.1 and R.sup.2 together with the nitrogen to which they are linked may form a 5- to 8- membered ring. PA1 .sup.8 is H, aryl or lower alkyl, preferably H, PA1 .sup.9 is H, OH or lower alkyl, preferably OH or H. PA1 R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or R.sup.1 and R.sup.2 together with the nitrogen to which they are linked may form a 5- to 8- membered ring. PA1 R.sup.2 is preferably H or phenyl. PA1 R.sup.7 is aryl or lower alkyl, preferably phenyl, PA1 R.sup.8 is H, aryl or lower alkyl, preferably H and PA1 R.sup.9 is H, OH or lower alkyl, preferably OH or H.
Misra et al disclose that these compounds may be prepared by transmetallating bromophenylalkyl B ##STR4## by treatment with t-C.sub.4 H.sub.9 Li or n-C.sub.4 H.sub.9 Li or subjecting B to a Grignard reaction by treatment with Mg, and then condensing with the perhydro benzopyran-3-ol derivative or the perhydro benzofuran-1-ol derivative C ##STR5## to form the condensed 7-oxabicycloheptane alcohol compound of the structure Z ##STR6## and then subjecting the condensed compound to hydrogenolysis to form the following alcohol ##STR7##
Where Pro is thexyldimethylsilyl or t-butyldimethylsilyl, the alcohol is acetylated and the silyl protecting group of the so-formed acetate is removed to form the following acetate: ##STR8## which is treated with a protecting compound and the acetate is removed by treatment with aqueous hydroxide or excess methyllithium to form the following alcohol: D' ##STR9## (where Pro is t-butyldiphenylsilyl). The protected alcohol is subjected to a Jones oxidation to form the following acid: ##STR10##
The so-formed carboxylic acid intermediate is then employed to make the final compound.
In a more preferred procedure, Misra et al disclose protecting the alcohol function of alcohol Z to form the protected alcohol ##STR11## subjecting the protected alcohol to a Jones oxidation and esterification to form the ester ##STR12## which is made to undergo hydrogenolysis and subsequent removal of the acetate protecting group by transesterification to afford the alcohol ##STR13## which is subjected to a Jones oxidation to form the carboxylic acid intermediate II ##STR14##
In an alternative procedure where n is 1, the above carboxylic acid intermediate II is formed by treating D' with acetic anhydride and removing the protecting group to form the acetate alcohol ##STR15## which is made to undergo a Dess-Martin oxidation to form the aldehyde ##STR16##
The above aldehyde is oxidized and esterified to the corresponding acetate ester, deprotected, and subjected to a Jones oxidation to form carboxylic acid II where n is 1.